This invention relates to methods for the preparation of porous inorganic shaped bodies especially calcium phosphate-containing shaped bodies; to the bodies thus prepared; and to methods for use thereof. In accordance with certain embodiments of this invention, shaped bodies are provided which are at once, highly porous and uniform in composition. They can be produced in a wide range of geometric configurations through novel, low temperature techniques. The shaped bodies of the invention can be highly and uniformly porous while being self-supporting. They can be strengthened further using a variety of techniques, thereby forming porous composite structures. Such porous structures are useful as cell growth scaffolds, bone grafting materials, drug delivery vehicles, biological separation/purification media, catalysis and other supports and in a wide range of other uses.
There has been a continuing need for improved methods for the preparation of mineral compositions, especially calcium phosphate-containing minerals. This long-felt need is reflected in part by the great amount of research found in the pertinent literature. While such interest and need stems from a number of industrial interests, the desire to provide materials which closely mimic mammalian bone for use in repair and replacement of such bone has been a major motivating force. Such minerals are principally calcium phosphate apatites as found in teeth and bones. For example, type-B carbonated hydroxyapatite [Ca5(PO4)3-x(CO3)x(OH)] is the principal mineral phase found in the body, with variations in protein and organic content determining the ultimate composition, crystal size, morphology, and structure of the body portions formed therefrom.
Calcium phosphate ceramics have been fabricated and implanted in mammals in various forms including, but not limited to, shaped bodies and cements. Different stoichiometric compositions such as hydroxyapatite (HAp), tricalcium phosphate (TCP), tetracalcium phosphate (TTCP), and other calcium phosphate salts and minerals, have all been employed to this end in an attempt to match the adaptability, biocompatibility, structure, and strength of natural bone. The role of pore size and porosity in promoting revascularization, healing, and remodeling of bone is now recognized as a critical property for bone replacement materials. Despite tremendous efforts directed to the preparation of porous calcium phosphate materials for such uses, significant shortcomings still remain. This invention overcomes those shortcomings and describes porous calcium phosphate and a wide variety of other inorganic materials which, in the case of calcium phosphates, closely resemble bone, and methods for the fabrication of such materials as shaped bodies for biological, chemical, industrial, and many other applications.
Early ceramic biomaterials exhibited problems derived from chemical and processing shortcomings that limited stoichiometric control, crystal morphology, surface properties, and, ultimately, reactivity in the body. Intensive milling and comminution of natural minerals of varying composition was required, followed by powder blending and ceramic processing at high temperatures to synthesize new phases for use in vivo.
A number of patents have issued which relate to ceramic biomaterials and are incorporated herein by reference. Among these are U.S. Pat. No. 4,880,610, B. R. Constantz ,xe2x80x9cIn situ calcium phosphate mineralsxe2x80x94method and composition;xe2x80x9d U.S. Pat. No. 5,047,031, B. R. Constantz, xe2x80x9cIn situ calcium phosphate minerals method;xe2x80x9d U.S. Pat. No. 5,129,905, B. R. Constantz, xe2x80x9cMethod for in situ prepared calcium phosphate minerals;xe2x80x9d U.S. Pat. No. 4,149,893, H. Aoki, et al, xe2x80x9cOrthopaedic and dental implant ceramic composition and process for preparing same;xe2x80x9d U.S. Pat. No. 4,612,053, W. E. Brown, et al, xe2x80x9cCombinations of sparingly soluble calcium phosphates in slurries and pastes as mineralizers and cements;xe2x80x9d U.S. Pat. No. 4,673,355, E. T. Farris, et al, xe2x80x9cSolid calcium phosphate materials;xe2x80x9d U.S. Pat. No. 4,849,193, J. W. Palmer, et al., xe2x80x9cProcess of preparing hydroxyapatite;xe2x80x9d U.S. Pat. No. 4,897,250, M. Sumita, xe2x80x9cProcess for producing calcium phosphate;xe2x80x9d U.S. Pat. No. 5,322,675, Y. Hakamatsuka, xe2x80x9cMethod of preparing calcium phosphate;xe2x80x9d U.S. Pat. No. 5,338,356, M. Hirano, et al xe2x80x9cCalcium phosphate granular cement and method for producing same;xe2x80x9d U.S. Pat. No. 5,427,754, F. Nagata, et al., xe2x80x9cMethod for production of platelike hydroxyapatite;xe2x80x9d U.S. Pat. No. 5,496,399, I. C. Ison, et al., xe2x80x9cStorage stable calcium phosphate cements;xe2x80x9d U.S. Pat. No. 5,522,893, L. C. Chow. et al., xe2x80x9cCalcium phosphate hydroxyapatite precursor and methods for making and using same;xe2x80x9d U.S. Pat. No. 5,545,254, L. C. Chow, et al., xe2x80x9cCalcium phosphate hydroxyapatite precursor and methods for making and using same;xe2x80x9d U.S. Pat. No. 3,679,360, B. Rubin, et al., xe2x80x9cProcess for the preparation of brushite crystals;xe2x80x9d U.S. Pat. No. 5,525,148, L. C. Chow, et al., xe2x80x9cSelf-setting calcium phosphate cements and methods for preparing and using them;xe2x80x9d U.S. Pat. No. 5,034,352, J. Vit, et al., xe2x80x9cCalcium phosphate materials;xe2x80x9d and U.S. Pat. No. 5,409,982, A. Imura, et al xe2x80x9cTetracalcium phosphate-based materials and process for their preparation.xe2x80x9d
Several patents describe the preparation of porous inorganic or ceramic structures using polymeric foams impregnated with a slurry of preformed ceramic particles. These are incorporated herein by reference: U.S. Pat. No. 3,833,386, L. L. Wood, et al, xe2x80x9cMethod of preparing porous ceramic structures by firing a polyurethane foam that is impregnated with inorganic material;xe2x80x9d U.S. Pat. No. 3,877,973, F. E. G. Ravault, xe2x80x9cTreatment of permeable materials;xe2x80x9d U.S. Pat. No. 3,907,579, F. E. G. Ravault, xe2x80x9cManufacture of porous ceramic materials;xe2x80x9d and U.S. Pat. No. 4,004,933, F. E. G. Ravault, xe2x80x9cProduction of porous ceramic materials.xe2x80x9d However, none of aforementioned art specifically describes the preparation of porous metal or calcium phosphates and none employs the methods of this invention.
The prior art also describes the use of solution impregnated-polymeric foams to produce porous ceramic articles and these are incorporated herein by reference: U.S. Pat. No. 3,090,094, K. Schwartzwalder, et al, xe2x80x9cMethod of making porous ceramic articles;xe2x80x9d U.S. Pat. No. 4,328,034 C. N. Ferguson, xe2x80x9cFoam Composition and Process;xe2x80x9d U.S. Pat. No. 4,859,383, M. E. Dillon, xe2x80x9cProcess of Producing a Composite Macrostructure of Organic and Inorganic Materials;xe2x80x9d U.S. Pat. No. 4,983,573, J. D. Bolt, et al, xe2x80x9cProcess for making 90xc2x0 K superconductors by impregnating cellulosic article with precursor solution;xe2x80x9d U.S. Pat. No. 5,219,829, G. Bauer, et al, xe2x80x9cProcess and apparatus for the preparation of pulverulent metal oxides for ceramic compositions;xe2x80x9d GB 2,260,538, P. Gant, xe2x80x9cPorous ceramics;xe2x80x9d U.S. Pat. No. 5,296,261, J. Bouet, et al, xe2x80x9cMethod of manufacturing a sponge-type support for an electrode in an electrochemical cell;xe2x80x9d U.S. Pat. No. 5,338,334, Y. S. Zhen, et al, xe2x80x9cProcess for preparing submicron/nanosize ceramic powders from precursors incorporated within a polymeric foam;xe2x80x9d and S. J. Powell and J. R. G. Evans, xe2x80x9cThe structure of ceramic foams prepared from polyurethane-ceramic suspensions,xe2x80x9d Materials and Manufacturing Processes, 10(4):757 (1995). The focus of this art is directed to the preparation of either metal or metal oxide foams and/or particles. None of the disclosures of these aforementioned references mentions in situ solid phase formation via redox precipitation reaction from homogeneous solution as a formative method.
The prior art also discloses certain methods for fabricating, inorganic shaped bodies using natural, organic objects. These fabrication methods, however, are not without drawbacks which include cracking upon drying the green body and/or upon firing. To alleviate these problems, the fabrication processes typically involve controlled temperature and pressure conditions to achieve the desired end product. In addition, prior fabrication methods may include the additional steps of extensive material preparation to achieve proper purity, particle size distribution and orientation, intermediate drying and radiation steps, and sintering at temperatures above the range desired for employment in the present invention. For example, U.S. Pat. No. 5,298,205 issued to Hayes et. al. entitled xe2x80x9cCeramic Filter Processxe2x80x9d, incorporated herein by reference, discloses a method of fabricating a porous ceramic body from an organic sponge saturated in an aqueous slurry comprised of gluten and particulate ceramic material fired at a temperature range from 1,100xc2x0 to 1,300xc2x0 C. Hayes teaches that the saturated sponge must be dehydrated prior to firing via microwave radiation, and includes a pre-soak heating step, and a hot pressing step.
While improvements have been made in materials synthesis and ceramic processing technology leading to porous ceramics and ceramic biomaterials, improved preparative methods, and the final products these methods yield, are still greatly desired. Generation of controlled porosity in ceramic biomaterials generally, and in calcium phosphate materials in particular, is crucial to the effective in vitro and in vivo use of these synthetic materials for regenerating human cells and tissues. This invention provides both novel, porous calcium phosphate materials and methods for preparing them. Methods relating to calcium phosphate-containing biomaterials, which exhibit improved biological properties, are also greatly desired despite the great efforts of others to achieve such improvements.
Accordingly, it is a principal object of this invention to provide improved inorganic, porous, shaped bodies, especially those formed of calcium phosphate.
A further object of the invention is to provide methods for forming such materials with improved yields, lower processing temperatures, greater compositional flexibility, and better control of porosity.
Yet another object provides materials with micro-, meso-, and macroporosity, as well as the ability to generate shaped porous solids having improved uniformity, biological activity, catalytic activity, and other properties.
Another object is to provide porous materials which are useful in the repair and/or replacement of bone in orthopaedic and dental procedures.
An additional object is to prepare a multiplicity of high purity, complex shaped objects, formed at temperatures below those commonly used in traditional firing methods.
Further objects will become apparent from a review of the present specification.
The present invention is directed to new inorganic bodies, especially controllably porous bodies, which can be formed into virtually any geometric shape. The novel preparative methods of the invention utilize redox precipitation chemistry or aqueous solution chemistry, which is described in pending U.S. patent application Ser. No. 08/784,439, U.S. Pat. No. 5,939,039 assigned to the present assignee and, incorporated herein by reference. In accordance with certain preferred embodiments, the redox precipitation chemistry is utilized in conjunction with a sacrificial, porous cellular support, such as an organic foam or sponge, to produce a porous inorganic product which faithfully replicates both the bulk geometric form as well as the macro-, meso-, and microstructure of the precursor organic support. The aqueous solution, because of its unique chemistry, has a high solids equivalent, yet can essentially be imbibed fully into and infiltrate thoroughly the microstructure of the sacrificial organic precursor material. This extent of infiltration allows the structural details and intricacies of the precursor organic foam materials to be reproduced to a degree heretofore unattainable. This great improvement can result in porous, inorganic materials having novel microstructural features and sufficient robustness to be handled as coherent bodies of highly porous solid.
The invention also gives rise to porous inorganic materials having improved compositional homogeneity, multiphasic character, and/or modified crystal structures at temperatures far lower than those required in conventional formation methods. In addition, the invention also gives rise to porous inorganic composites comprising mineral scaffolds strengthened and/or reinforced with polymers, especially film-forming polymers, such as gelatin.
The new paradigm created by this invention is facilitated by a definition of terms used in the description of embodiments. The general method starts with infiltrant solutions produced from raw materials described herein as salts, aqueous solutions of salts, stable hydrosols or other stable dispersions, and/or inorganic acids. The sacrificial, porous organic templates used in some embodiments may be organic foams, cellular solids and the like, especially open-cell hydrophilic material which can imbibe the aqueous infiltrant solutions. Both the precursor organic templates, as well as the inorganic replicas produced in accordance within this invention, display a porosity range of at least 3 orders of magnitude. This range of porosity can be described as macro-, meso- and microporous. Within the scope of this invention, macroporosity is defined as having a pore diameter greater than or equal to 100 microns, mesoporosity is defined as having a pore diameter less than 100 microns but greater than or equal to 10 microns, and microporosity is defined as having a pore diameter less than 10 microns.
In addition to the controlled macro-, meso- and microporosity ranges, inorganic shaped bodies have been fabricated possessing pore volumes of at least about 30%. In preferred embodiments, pore volumes of over 50% have been attained and pore volumes in excess of 70% or 80% are more preferred. Materials having macro-, meso- and microporosity together with pore volumes of at least about 90% can be made as can those having pore volumes over 92% and even 94%. In some cases, pore volumes approaching 95% have been ascertained in products which, nevertheless, retain their structural integrity and pore structure.
The phases produced by the methods of this invention [Redox Precipitation Reaction (RPR) and HYdrothermal PRocessing (HYPR)] initially are intermediate or precursor minerals, which can be easily converted to a myriad of pure and multiphasic minerals of previously known and, in some cases, heretofore undefined stoichiometry, generally via a thermal treatment under modest firing regimens compared to known and practiced conventional art.
In accordance with certain embodiments of the present invention, methods are provided for the restoration of bony tissue. In this regard, an area of bony tissue requiring repair as a result of disease, injury, desired reconfiguration and the like, is identified and preferably measured. A block of porous calcium phosphate material can be made to fit the dimensions of the missing or damaged bony tissue and implanted in place by itself or in conjunction with biocompatible bonding material compositions such as those disclosed in U.S. Pat. No. 5,681,872 issued in the name of E. M. Erbe on Oct. 28, 1997 and incorporated herein by reference. The calcium phosphate material can also be used as a xe2x80x9csleevexe2x80x9d or form for other implants, as a containment vessel for the bone grafting material which is introduced into the sleeve for the repair, and in many other contexts.
A major advantage of the restoration is that after polymerization, it has a significant, inherent strength, such that restoration of load-bearing bony sites can be achieved. While immobilization of the effected part will likely still be required, the present invention permits the restoration of many additional bony areas than has been achievable heretofore. Further, since the porous calcium phosphate scaffolding material of the present invention is biocompatible and, indeed, bioactive, osteogenesis can occur. This leads to bone infiltration and replacement of the calcium phosphate matrix with autologous bone tissue.
The calcium phosphate scaffolding material of the present invention may also be made into shaped bodies for a variety of uses. Thus, orthopaedic appliances such as joints, rods, pins, or screws for orthopaedic surgery, plates, sheets, and a number of other shapes may be formed from the material in and of itself or used in conjunction with conventional appliances that are known in the art. Such hardened compositions can be bioactive and can be used, preferably in conjunction with hardenable compositions in accordance with the present invention in the form of gels, pastes, or fluids, in surgical techniques. Thus, a screw or pin can be inserted into a broken bone in the same way that metal screws and pins are currently inserted, using conventional bone cements or restoratives in accordance with the present invention or otherwise. The bioactivity of the present hardenable materials give rise to osteogenesis, with beneficial medical or surgical results.
The methods of the invention are energy efficient, being performed at relatively low temperature; have high yields; and are amenable to careful control of product shape, macro- and microstructure, porosity, and chemical purity. Employment as bioactive ceramics is a principal, anticipated use for the materials of the invention, with improved properties being extant. Other uses of the porous minerals and processes for making the same are also within the spirit of the invention.
The present invention also provides exceptionally fine, uniform powders of inorganic materials. Such powders have uniform morphology, uniform composition and narrow size distribution. They may be attained through the comminution of shaped bodies in accordance with the invention and have wide utility in chemistry, industry, medicine and otherwise.